tbuckley/cabot-search huggingface dataset:
A combined phase I/II study of a novel bicycle tumor-targeted immune cell agonist BT7480 in patients with nectin-4 associated advanced malignancies.
Authors: Kyriakos P. Papadopoulos, Afshin Dowlati, Amy Dickson, Sandra Hirschberg, Sally Westrup, Punit Upadhyaya, Heather Cohen, Kristen Hurov, Roshawn Watson, Sebastien Hazard, Dominic Smethurst, Jordi Rodon Ahnert
Journal: Journal of Clinical Oncology (2022)

TPS2689 Background: BT7480 is a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist ( Bicycle TICA) that co-ligates cluster of differentiation (CD)137 (on immune cells) and Nectin-4 (on tumor cells). BT7480 comprises 3 bicyclic peptides ( Bicycles), 1 that binds to Nectin-4 and 2 that bind to CD137. The Bicycles are conjugated via a branched trimeric polyethylene glycol linker. Co-ligation of Nectin-4 and CD137 by BT7480 is hypothesized to induce oligomerization and activation of CD137 resulting in a tumor-localized costimulatory signal that leads to an antitumor response in preclinical studies. Nectin-4 is reported to be highly expressed in numerous tumors with unmet medical need including bladder, pancreas, breast, ovary, esophagus, head and neck, stomach, and lung cancers. Many of these tumor types also contain CD137 expressing cells. BT7480 exhibited a favorable preclinical profile supporting initiation of a first-in-human study to investigate safety and efficacy in indications with evidence of Nectin-4 expression. Methods: BT7480-100 (NCT05163041) is a PhI/II study to evaluate safety and tolerability of BT7480 administered as an intravenous infusion QW in a 28-day cycle, and to determine a recommended Phase 2 dose to further explore efficacy and safety. Patients will be recruited with advanced solid tumors associated with Nectin-4 expression including urothelial; head and neck squamous cell; non-small cell lung; ovarian, breast, gastric or esophageal carcinoma after exhausting standard of care options. Patients must have available tumor tissue, acceptable hematologic and other critical organ function. Exclusion criteria include uncontrolled brain metastases, uncontrolled hypertension, significant history of autoimmune disease and prior CD137 targeted therapy. Pharmacokinetic and pharmacodynamic analyses will be performed to support dose escalation decisions and increase the understanding of safety and clinical activity signals observed during the study. Tumor response will be assessed per RECIST every 8 weeks. Cohorts 1 and 2 have been completed without DLT. Enrollment in cohort 3 began in January 2022. Clinical trial information: NCT05163041.
A randomized phase II study of anlotinib combined with STUPP versus STUPP alone in patients with newly diagnosed glioblastoma (GBM).
Authors: Yuan yuan Yuan Chen, Baiqiang Dong, Zhongping Chen
Journal: Journal of Clinical Oncology (2022)

TPS2079 Background: Postoperative with radiotherapy, and concomitant and up to 6 cycles of maintenance temozolomide (TMZ) chemotherapy (STUPP regimen) is now the standard treatment for newly diagnosed GBM, while the effectiveness is limited. Anlotinib is a novel, multi-kinase inhibitor against both tumor angiogenesis and tumor cell proliferation with encouraging findings in preclinical GBM models. Our previous single-arm study (NCT04119674) showed that the addition of anlotinb to STUPP exhibited promising progression-free survival (PFS) in patients with GBM. Therefore, a phase II trial was designed to assessed the efficacy and safety of anlotinib with the STUPP regimen. Methods: This is a multicenter, randomized, controlled, phase II superiority trial. Approximately 150 patients will be randomly assigned 1:1 to receive TMZ-based radiochemotherapy with anlotinib or TMZ-based radiochemotherapy with placebo. All patients will receive radiotherapy (fractionated focal irradiation in daily fractions of 1.8–2.0 Gy given 5 days per week for 6 weeks, for a total of 54–60 Gy) concurrently with TMZ (75 mg/m2 QD) and anlotinib (10 mg QD, d1–14/3wks) or placebo. Anlotinib or placebo is administrated during the 28-day treatment break. Adjuvant therapy start four weeks after radiotherapy completion, including six cycles of TMZ (150–200mg/m2, d1–5/4wks) and eight cycles of anlotinib (10 mg QD, d1–14/3wks) or placebo. Patients who complete adjuvant therapy are administrated anlotinib or placebo continuously until the disease progressed or unacceptable toxic effects developed. Eligibility criteria include histologically confirmed newly diagnosed GBM and a World Health Organization (WHO) performance status ≤ 2. Additional inclusion criteria include patients between 18 and 75 years old with adequate wound healing of craniotomy or biopsy; adequate hematologic, hepatic, and renal function; acceptable blood coagulation levels; and the stable or decreasing usage of glucocorticoid doses within 5 days before randomization. Exclusion criteria include potentially fatal intracranial hemorrhage on magnetic resonance imaging (MRI); tumors located only in the brainstem; prior chemotherapy or radiotherapy administered for GBM; and IDH1/2 mutation. The primary objective of this study is to compare PFS accessed by Independent Review Committee in patients receiving anlotinib in addition to standard treatment with patients receiving standard treatment only. Secondary endpoints include overall survival (OS), PFS accessed by investigators, overall response rate (ORR), severity and frequency of AEs (CTCAE V5.0), and quality of life (QOL). The disease control rate (DCR) and duration of response (DOR) will also be explored. Clinical trial information: NCT04959500. Research Sponsor: Chia Tai Tianqing Pharmaceutical Group Co., Ltd .
<i>MAP3K8</i> and <i>ALK</i> alterations in pediatric patients with atypical Spitz tumors and Spitz melanoma.
Authors: Maggie Nagel, Xiaomeng Yuan, Valerie McPherson, Armita Bahrami, Alberto S. Pappo
Journal: Journal of Clinical Oncology (2022)

e21569 Background: Pediatric atypical Spitz tumors and Spitz melanoma (AST/SM) are characterized by structural variants (rearrangements/truncations) of various kinase genes more commonly involving MAP3K8 and ALK. The clinical features associated with these genomic abnormalities have not been well characterized. Methods: We reviewed the clinical characteristics and outcomes of children and adolescents with AST/SM who were enrolled on our institutional comprehensive registry for melanocytic lesions MACMEL (Cancer 127:3825, 2021) and abstracted clinical and outcome data for patients with MAP3K8, ALK, and other less common genomic aberrations. Results: Table shows the characteristics and outcomes of patients with AST/SM who had MAP3K8, ALK, and other genomic aberrations. There were 49 patients of whom 21 had MAP3K8 rearrangements/ truncations (n = 11;22%) or ALK rearrangements (n = 10;20%). The remaining 28 patients had fusions involving ARAF (1), ROS1 (2), NTRK1 (3), ERBB2 (1) or rare mutations (ATM = 1) or copy number changes (n = 14) or no identifiable genomic abnormality (n = 6). Female sex was more common in all three groups (32 female and 17 male). The median age for the entire cohort was 7.5 years. Most lesions arose in the extremities (n = 32; 65%). About half had stage III disease. 40 patients underwent sentinel node biopsy (SLNB), 25 had at least one positive node (7/9 MAP3K8, 5/8 ALK, 13/23 other), Forty-four patients had FISH analysis for CDKN2A and homozygous loss was seen in 9/11 MAP3K8-rearranged, 2/6 ALK-rearranged, and 11/27 other tumors. No TERT promoter mutation was detected in any of the 45 tumors that were analyzed. Two patients experienced local recurrence, one with a MAP3K8-STX fusion and one with a FLOT2-ARAF fusion and activating RAC1 mutation. All patients are alive and currently disease free (median follow up of 2.33 years). There were no statistically significant associations between gene mutations and tumor site, gender, or stage. Conclusions: Approximately 40% of patients with AST/SM harbored ALK or MAP3K8 alterations in our pediatric melanoma registry. We found no significant association between the individual genes and any specific clinical features in this limited cohort.[Table: see text]
Phase I study of entinostat (Ent), atezolizumab (A), carboplatin (C), and etoposide (E) in previously untreated extensive-stage small cell lung cancer (ES-SCLC), ETCTN 10399.
Authors: Ryan D. Gentzler, Richard Piekarz, Liza C Villaruz, John C. Rhee, Wei-Chu Victoria Lai, Bethany Horton, Joseph Mock, Michael Hanley, Michelle A. Rudek, Mitch A. Phelps, Michael Anthony Carducci, Charles M. Rudin
Journal: Journal of Clinical Oncology (2022)

e20606 Background: A-CE has demonstrated improved overall survival in ES-SCLC, but there are currently no approved therapies targeting genomic alterations in SCLC. Mutations in acetyltransferases CREBBP and EP300 occur at a frequency of 15% and 13%, respectively, in SCLC, and PDX models with CREBBP mutations were demonstrated to be susceptible to targeting with HDAC inhibitors. Ent, a class I selective HDAC inhibitor, has also demonstrated clinical activity in a combination with pembrolizumab in patients with NSCLC and uveal melanoma with minimal hematologic toxicity at RP2D of 5 mg PO weekly. We conducted a phase I trial to evaluate the combination of Ent with A-CE for ES-SCLC, NCI ETCTN 10399. Methods: Patients (pts) with treatment-naïve ES-SCLC, stable or treated brain metastases, ECOG ≤2 were enrolled and treated on up to 4 dose levels of Ent. Allocation to cohorts was determined using Bayesian optimal interval (BOIN) design targeting a MTD with a DLT rate of 20%. Dose levels (DL) included Ent 2 mg, 3 mg, or 5 mg PO weekly on day (d) 1 in addition to 4 cycles of A-CE (A 1200 mg, C AUC 5, E 100 mg/m2 d 1-3) followed E+A for 1 year. Pre-treatment tissue and plasma collected for WES. Results: 3 pts were enrolled and treated at DL1 with Ent 2 mg. Pts were age 69-83, 2 male, 1 female, 2 were ECOG 1, 1 was ECOG 0, and 1 with prior SRS radiation for brain metastases. 2 of 3 experienced DLTs during cycle 1: (1) Grade (Gr) 4 febrile neutropenia after 2 doses of Ent and (1) Gr 5 sepsis after 1 dose of Ent. BOIN design required stopping accrual to dose level 1 and the trial was closed to further accrual. The pt without DLT experienced grade 3 thrombocytopenia after 2 doses of Ent, but recovered after holding cycle 1, day 15 Ent. This patient experienced Gr 3 neutropenia during cycle 2. The most common adverse events were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), hypocalcemia (2). Of these, most were Gr 3-4: anemia (1), neutropenia (3), thrombocytopenia (2), leukopenia (1), hypocalcemia (1). Conclusions: The combination of low dose Ent 2 mg PO weekly + AC-E is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia in the first 1-2 weeks and ≥Gr 3 neutropenia and thrombocytopenia prior to completing 2 cycles of treatment for all pts. There is no role for further exploration of entinostat with carboplatin, etoposide, and atezolizumab. Clinical trial information: NCT04631029.
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) compared to computed tomography (CT) for advanced renal cell carcinoma (RCC).
Authors: Shivanshan Pathmanathan, Arsalan Tariq, Chun Loo Gan, Adam Pearce, Handoo Rhee, Samuel Kyle, Sheliyan Raveenthiran, David Wong, Rhiannon McBean, Philip Marsh, Steven Goodman, Nattakorn Dhiantravan, Rachel Esler, Nigel Dunglison, Anojan Navaratnam, John Yaxley, Paul Thomas, David A. Pattison, Jeffrey C. Goh, Matthew Roberts
Journal: Journal of Clinical Oncology (2022)

4540 Background: There is emerging role of the use of PSMA PET in RCC. Herein, we report our experience in use of PSMA PET in recurrent or metastatic RCC in Brisbane, Australia. Methods: Patients (pts) who underwent PSMA PET and conventional diagnostic CT for metastatic or recurrent RCC between 2015 and 2020 at three institutions were identified. Retrospective chart reviews were conducted using standardized collection template. The outcomes included percentage of patients who had a change in management secondary to PSMA PET findings, comparison of metastasis detection for PSMA PET vs. CT, and biopsy histology of PSMA avid sites. Results: 42 PSMA PET were performed in 40 patients. 10 pts (25%) and 30 pts (75%) had PSMA PET in the metastatic disease and recurrent disease setting, respectively. Table 1 highlights demographics. Overall, 12 pts (30%, n=3 metastatic, n=9 recurrent) had a change in management following PSMA PET. In the metastatic disease group, 2 pts (20%) underwent initial systemic therapy (after histological confirmation) due to higher burden of disease shown with PSMA PET than CT, while systemic therapy was changed for 1 pt (10%). In the recurrent disease group, PSMA improved delineation of suspected recurrence (compared to CT) resulting in resection rather than surveillance (n=4; 13%) or change in surgical approach for resection (n=1; 3%). PSMA PET distribution showed more metastatic sites than CT leading to systemic therapy rather than resection of recurrence (n=2; 7%), while absent PSMA activity for suspected recurrence on CT led to surveillance rather than resection (n=2; 7%). PSMA PET detected more sites of metastases compared with conventional scan in 6 pts (60%) with metastatic disease and in 9 pts (30%) with recurrent disease. 26 pts had biopsy of PSMA avid sites. Majority of pts had confirmed recurrence of clear cell renal carcinoma (n= 22; 85%). Other histology included sarcomatoid renal cell carcinoma (n=2; 8%), carcinoid (n=1; 4%), and urothelial cancer (n=1; 4%). In 2 instances, biopsy/resection was performed of a suspected recurrence on CT that was not PSMA avid, and neither showed malignancy. Conclusions: PSMA PET detected more accurately metastatic and recurrent disease, with high pathological concordance, to result in change in management for 30% of patients. Prospective study is warranted to further investigate the utility of PSMA PET scan in advanced RCC.[Table: see text]
Effect of plasma fibrinogen on the curative effect and prognosis of locally advanced oropharyngeal cancer after induction chemotherapy.
Authors: Li yuan-yuan Wu wei-li JIN feng
Journal: Journal of Clinical Oncology (2022)

e18062 Background: To investigate the effect of plasma fibrinogen on the curative effect and prognosis of locally advanced oropharyngeal cancer after induction chemotherapy. Methods: Data from 52 patients with locally advanced oropharyngeal cancer who received sequential chemoradiotherapy with induction chemotherapy were retrospectively analyzed. Univariate and multivariate analyses were performed based on logistic regression models to identify clinicopathological factors associated with the efficacy of induction chemotherapy. Cox regression model was used to determine the correlation between clinical or pathological parameters and overall survival (OS) and progression-free survival (PFS). Kaplan-meier test and log-rank test were used for survival analysis. Results: ROC curve was used to determine the optimal threshold of response after induction chemotherapy. Patients were divided into low Fib group and high Fib group (Fib≤4.01g/L and ＞4.01g/L).The proportion of stage IVb and P16 negative in the high Fib group was higher than that in the low Fib group (55.6% vs 29.4%, P= 0.027; 72.2% vs 47.1%, P = 0.082) .Regarding overall response, 42(80.8%)patients responded to IC and 10(19.2%)patients did not respond.The proportion of stage IVb and p16 negative in the non-responding group was higher than that in the responding group (80% vs 28.6%, χ 2 = 9.026, P= 0.003; 90% vs 47.6%, χ 2 = 5.881, P= 0.015).In logistic regression model, high Fib level was significantly correlated with no response to induction chemotherapy (OR = 6.946, 95% CI 1.015̃47.516, P = 0.048). Multivariate analysis showed that total stage, P16 status and plasma Fib level before treatment were independent influencing factors of OS and PFS. The 3-year OS and PFS in pre-treatment high Fib group was significantly lower than that of the low Fib group ( P&lt; 0.001, P = 0.005) .Responding to induction chemotherapy was independent influencing factors of PFS. The 3-year OS and PFS in the responding group was significantly higher than that in the non-responding group (65.2% vs 12.7%, P&lt; 0.001; 64.5% vs 12.2%, P= 0.015). Conclusions: Responding to induction chemotherapy was independent influencing factors of PFS.High plasma Fib(Fib＞4.01g/L) was significantly associated with no response to locally advanced oropharyngeal cancer after induction chemotherapy. In addition, patients with pre-treatment high Fib level had significantly lower OS and PFS than those with low Fib level.
Impact of broadening trial eligibility criteria on the inclusion of patients with brain metastases in cancer clinical trials.
Authors: Joseph M. Unger, Hong Xiao, Dawn L. Hershman, Riha Vaidya
Journal: Journal of Clinical Oncology (2022)

1505 Background: On October 2, 2017, the American Society of Clinical Oncology, Friends of Cancer Research, and the U.S. Food and Drug Administration (ASCO/FoCR/FDA) issued a joint research statement recommending that certain eligibility criteria in cancer clinical trials, including those related to brain metastases, be broadened to make trials more inclusive. We examined whether patterns of exclusions regarding patients with brain metastases changed over time in relation to these recommendations. Methods: We used data from ClinicalTrials.gov to evaluate patterns of trial eligibility criteria in phase I-III U.S.-based interventional clinical trials for patients with advanced breast, colorectal, or lung cancers from January 2013 through October 2021. Trial inclusion and exclusion criteria were abstracted; to enhance validity, reviewers were blinded to the year of trial activation. For each trial, we determined whether patients with brain metastases were not excluded, conditionally excluded (i.e., excluded in some circumstances), or wholly excluded. Trial registrations between October 2, 2017-December 31, 2018 were excluded to allow 1 year for newly conceived trials to adopt the recommendations, plus 3 months to account for the lag time between loading trial records and trial activation dates; thus, the independent exposure variable was January 1, 2019. An interrupted time series analysis with multinomial logistic regression was used to assess whether the ASCO/FoCR/FDA recommendations were associated with changes in brain metastases eligibility criteria. Results: We evaluated N = 1998 trials. Patients with brain metastases were not excluded in 307 trials (15.4%); conditionally excluded in 1459 trials (74.8%); and wholly excluded in 196 trials (9.8%). In the post-recommendation period, we found a 92% increase in the odds of trials with brain metastases not excluded compared to conditionally excluded (OR = 1.92, 95% CI, 1.08-3.45, p =.03). The estimated proportion of trials in which patients with brain metastases were not excluded increased from 9.2% had the recommendations not been made to 15.6% (p =.04). Conversely, the proportion of trials in which patients with brain metastases were conditionally excluded (76.9%) was lower than expected (85.3%, p =.02). We found no difference in the proportion of trials in which patients with brain metastases were wholly excluded (7.5% vs. 5.4%, p =.28). Conclusions: The ASCO/FoCR/FDA recommendations were associated with a shift in patterns of brain metastases exclusion criteria from conditionally excluded to not excluded. To our knowledge, this is the first evidence that cancer clinical trials have become more inclusive of a broader set of patients in response to the ASCO/FoCR/FDA recommendations. More inclusive eligibility improves trial access and representativeness, increasing trial validity and the pace at which trials enroll.
Automated tumor immunophenotyping and response to immunotherapy in non-small cell lung cancer using a spatial statistics approach.
Authors: Darya Orlova, Xiao Li, Jefferey Eastham-Anderson, Wei Zou, Evgeniy Tabatsky, Jennifer M. Giltnane, Namrata S. Patil, Maureen Peterson, Andries Zijlstra, Hartmut Koeppen
Journal: Journal of Clinical Oncology (2022)

2626 Background: Based on the clinical success of immuno-oncology therapeutics, tissue-based, biomarker analyses have shifted from a focus on tumor cell phenotypes to spatial and functional analyses of the tumor immune environment. Distribution and composition of immune infiltrates have shown prognostic or predictive value in various studies; however, standardized approaches to categorize tumors into “Desert”, “Excluded” or “Inflamed” immunophenotypes based on the density and pattern of immune infiltrates are missing. This categorization is typically based on visual inspection of a stained tissue section; it is labor-intensive and associated with poor inter-observer concordance. To eliminate these barriers we developed an automated approach that relies on a set of derived spatial features and named this analysis pipeline LATIS (metric Learning based Automated Tumor Immunophenotyping with Spatial statistics). Methods: We used two clinical trials, POPLAR (phase II; n=258) and OAK (phase III; n=623) that compared anti-PD-L1 treatment vs chemotherapy in patients with advanced non-small cell lung cancer to develop and validate this approach. LATIS utilizes scans of slides stained immunohistochemically for CD8 and cytokeratin (CK); images were tiled and classified according to CK status (positive/negative). First, CD8 positive and CK density was calculated for each tile. Twenty six spatial features were then extracted for each tiled image scan. We used a labeled (manual immunophenotype calls) POPLAR dataset to learn a metric that separates classes of labeled data best with respect of spatial features provided for each data point. Then, to co-embed OAK dataset with POPLAR dataset into the same space, we used that learned metric as a measure of distance between new unlabeled points (OAK data set). K-means clustering in the embedded space was used to identify clusters of data points followed by QFMatch to assign class labels (“Inflamed”, “Excluded”, “Desert”) to each data point. Results: LATIS successfully relates spatial features to both, manual reads and patient response to therapy. In OAK, anti-PD-L1 treated patients experienced longer median overall survival (OS) when tumors showed intra-epithelial CD8+ cells (Inflamed) compared to tumors with a stromal pattern of CD8+ cells (Excluded) or a low density of CD8+ cells (Desert): 17.6 months vs 10.3 (Excluded) vs 12.1 (Desert) [p=0.0061]. Median progression-free survival (PFS) was 3.2 months (Inflamed) vs 2.6 (Excluded) vs 1.4 (Desert) [p=0.00058]. OS and PFS were not significantly different for the three categories in chemotherapy only arm. Conclusions: We suggest that tumor immunophenotype categories generated in an automated fashion by LATIS can serve as predictive biomarker for cancer immunotherapy.